Physical exercise exerts a salutary effect on the onset, progression, and severity of type 2 diabetes. However, little is known regarding the mechanisms underlying the beneficial effects of exercise on skeletal muscle. Recent studies have suggested a role for the stress-activated kinase, c-jun-NH2-terminal kinase isoform 1 (JNK1), in the regulation of whole body glucose metabolism. It is currently not known whether the effects of JNK1 signaling are mediated via alterations in glucose metabolism in skeletal muscle. The overall goal of this proposal is to determine the physiological consequences of JNK1 signaling on skeletal muscle responses to insulin and acute bouts of exercise. Specifically, the experiments outlined in this proposal will test the hypothesis that JNK1 deficiency alters the ability of insulin and exercise to regulate skeletal muscle glucose uptake, glycogen synthesis, and intracellular signaling proteins involved in glucose metabolism. Ultimately, these studies will help to define the molecular mechanisms underlying type 2 diabetes and the beneficial effects of physical exercise on skeletal muscle glucose metabolism. Also, these studies may uncover new pharmacological targets for the treatment of type 2 diabetes.